Project Summary Chronic Kidney Disease (CKD) affects 1 out of 5 older adults in the US including more than 400,000 older veterans yet is often unrecognized by affected individuals and even their healthcare providers. Older adults with CKD suffer from a markedly higher risk of cognitive and physical dysfunction, including a 40% greater risk of dementia and a 75% greater risk of physical frailty. The factors which account for this risk are unclear; however, recent neuroimaging investigations suggest a greatly increased burden of covert brain pathology in association with CKD and reduced kidney function. Outside the context of CKD, these neuroimaging findings of subclinical ischemic brain disease - silent brain infarcts, white matter hyperintensities, atrophy, and hypoperfusion - are associated with reduced cognitive and physical function. However, there has been no formal statistical evaluation of subclinical ischemic brain disease as a mediator of the relations of CKD to physical and cognitive function, nor any investigations of the patterns of cognitive and physical dysfunction in older adults with CKD. We hypothesize that older veterans with CKD suffer from a greater burden of subclinical ischemic disease of the brain, which results in impaired neurocognition and physical function. In this revised proposal, we will conduct an observational cohort study of stroke-free community-dwelling older veterans (ages 60-85) with CKD not requiring dialysis (N=150, evenly distributed among mild, moderate and severe CKD), and a control group without CKD but frequency-matched on the common co-morbid conditions diabetes, hypertension and cardiac disease (N=50). We will obtain quantitative measurements of 1) kidney disease and function (including albuminuria and the renal biomarker cystatin C), 2) ischemic brain disease using MRI, 3) physical function and performance, and 4) multiple domains of neurocognitive function. The overall aims are to estimate the association of CKD and renal function measures with MRI-defined subclinical ischemic brain disease and cognitive and physical function. Multivariate analyses will be employed to identify patterns of functional deficits and alterations of brain structure in CKD. Structural equations models (SEM) will examine whether subclinical ischemic brain disease mediates the relations of CKD and associated renal function measures to neurocognition and physical function after accounting for major co-morbid conditions including hypertension, diabetes, and cardiac disease. Results of this investigation will be of critical importance in the development of methods to detect and ultimately prevent functional deficits among older adults with CKD, a highly prevalent and rapidly growing population. PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease (CKD) affects over 400,000 older veterans yet is frequently unrecognized. Older patients with CKD are at markedly higher risk for physical and cognitive deficit, but the specific patterns of deficits and the mechanisms which account for them are uncertain. However, there is increasing evidence that CKD patients have an increased risk of covert vascular disease of the brain, which could have adverse effects on brain function. The proposed research will study older veterans with and without chronic kidney disease to characterize the patterns of deficits in physical function and cognition associated with kidney disease, and examine whether an increased burden of covert vascular disease on brain imaging accounts for these deficits related to CKD. These investigations are the first steps in efforts to preserve brain function in older veterans with CKD, a large and under-recognized population.